Perinatal arterial stroke (PAS) includes infants with neonatal arterial ischemic stroke and presumed perinatal arterial stroke and has an estimated incidence of 1 in 1150. The majority will develop hemiparesis, often resulting in lifelong and debilitating disability, including lowered cognition and quality of life. There are no evidence-based forms of rehabilitation designated as standard-of-care for these infants. We propose a Phase III trial to address this lack of evidence-based treatments. The I-ACQUIRE Trial is a rigorous, adequately powered, multi-site randomized controlled trial comparing 2 dosages of a pediatric rehabilitation - known as Infant ACQUIRE - to Usual and Customary treatment (U&CT). Prior studies of I- ACQUIRE show high safety, patient acceptability, and evidence of significant and enduring benefits. Briefly, I- ACQUIRE will be used to treat 8 ? 24 mth old infants with PAS in either 3 hrs/day (Moderate Dose) or 6 hrs/day (High Dose), for 5 days/wk for 4 wks. Treatment occurs in a home or natural setting where operant conditioning techniques are applied to achieve goals paced for each infant. I-ACQUIRE includes the core features of pediatric Constraint-Induced Movement Therapy (CIMT). Standardized treatment at all sites is monitored weekly via a Fidelity of CIMT Implementation tool. Clinical Trial Design: 240 infants (N=80/group) will be randomly assigned to: 1) Moderate Dose I-ACQUIRE, 2) High Dose I-ACQUIRE, or 3) U&CT. (N=80). Double-blinded assessments occur at baseline, end of 4 wks of treatment, and 6 mos post-treatment. A Parent Council will be active throughout the trial, supporting NIH's goal of increased stakeholder engagement in clinical trials. The specific aims are: 1) Primary: Determine the efficacy of I-ACQUIRE at 2 dosage levels compared to U&CT to increase upper extremity skills on the hemiparetic side (using a minimal clinically meaningful threshold that is achieved at end of treatment and 6 mos later); 2) Secondary: Determine the efficacy of I- ACQUIRE at 2 dosage levels compared to U&CT to improve use of the hemiparetic upper extremity as an ?assisting hand? in bimanual activities; and 3) Exploratory: Explore the association between I-ACQUIRE treatment at Moderate and/or High Doses and the infant's gross motor development and cognition (i.e., potential cross-domain effects of treatment). The Statistical Analysis Plan controls for multiple comparisons; after testing the major study hypotheses, sensitivity analyses will consider factors that may contribute to variation in treatment outcomes. Public Health Impact: Each year, an estimated 3400+ infants in the U.S. have PAS with high likelihood of lifelong impairment in neuromotor and often cognitive functioning resulting in a high cost burden for families, the healthcare system, and society. If I-ACQUIRE proves efficacious, then the field will have the critically needed Phase III confirmatory evidence and the specific clinical protocol needed to transform rehabilitation and improve clinical outcomes and quality of life for infants with PAS.